PDE10 is known to be a dual cAMP/cGMP phosphodiesterase; see, for example, Kehler et al, “The potential therapeutic use of phosphodiesterase 10 inhibitors”, Expert Opin. Ther. Patents (2007) 17(2):147-158.
PDE10 is expressed at high levels in all striatal medium spiny neurons (MSNs), but is expressed at much lower or undetectable levels elsewhere in the brain and periphery. By increasing cAMP and cGMP levels in all striatal MSNs, PDE10 inhibition will mimic D2 dopamine receptor antagonism in the indirect striatopallidal output pathway and will increase the activity of the direct striatonigral output pathway, thus more fully normalizing the reduced striatal output that characterizes schizophrenia. By increasing corticostriatal transmission, PDE10 inhibition should improve the cognitive dysfunction that characterizes schizophrenia. Furthermore, the discrete localization of PDE10 should lead to an improved side effect profile; typical side effects include extrapyramidal syndrome, diabetes, weight gain, hyperprolactinemia, sedation and QTc prolongation.
PDE10 inhibitors have also been reported to be useful in treating in other CNS (central nervous system) disorders such as psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet-induced obesity, diabetes and metabolic syndrome.
Papaverine has been identified as a PDE10 inhibitor, and has been shown to be effective in animal models of schizophrenia.
8-Substituted triazolopyridine phosphodiesterase 4 inhibitors useful in the treatment of skin diseases are disclosed in WO 2008/125111. 6,7-Di-aryl/heteroaryl-substituted triazolopyridines are disclosed in US 2006/0287324. 6-Aminomethyl-substituted triazolopyridines and derivatives thereof are disclosed in WO 2007/113226. Imidazo- and triazolopyridine keratin dyeing compounds are disclosed in US 2005/0229333. Imidazo- and triazolopyridines useful in treating diseases associated with 11-beta-hydroxysteroid dehydrogenase type I are disclosed in WO 2006/135795. Imidazopyridines having phosphatidylinositol 3 kinase inhibitory activity are disclosed in EP 1277754.